Pharmacometrics of high dose ivermectin in early COVID-19: an open label, randomized, controlled adaptive platform trial (PLATCOV)
- Mahidol University, Thailand
- Oxford University Clinical Research Unit, United Kingdom
- Ministry of Public Health, Thailand
- Navamindradhiraj University, Thailand
- Universidade Federal de Minas Gerais, Brazil
Abstract
Background: There is no generally accepted methodology for in vivo assessment of antiviral activity in SARS-CoV-2 infections. Ivermectin has been recommended widely as a treatment of COVID-19, but whether it has clinically significant antiviral activity in vivo is uncertain.
Methods: In a multicentre open label, randomized, controlled adaptive platform trial, adult patients with early symptomatic COVID-19 were randomized to one of six treatment arms including high dose oral ivermectin (600µg/kg daily for seven days), the monoclonal antibodies casirivimab and imdevimab (600mg/600mg), and no study drug. The primary outcome was the comparison of viral clearance rates in the modified intention-to-treat population (mITT). This was derived from daily log10 viral densities in standardized duplicate oropharyngeal swab eluates. This ongoing trial is registered at ClinicalTrials.gov (NCT05041907).
Results: Randomization to the ivermectin arm was stopped after enrolling 205 patients into all arms, as the prespecified futility threshold was reached. Following ivermectin the mean estimated rate of SARS-CoV-2 viral clearance was 9.1% slower [95%CI -27.2% to +11.8%; n=45] than in the no drug arm [n=41], whereas in a preliminary analysis of the casirivimab/imdevimab arm it was 52.3% faster [95%CI +7.0% to +115.1%; n=10 (Delta variant) versus n=41].
Conclusions: High dose ivermectin did not have measurable antiviral activity in early symptomatic COVID-19. Pharmacometric evaluation of viral clearance rate from frequent serial oropharyngeal qPCR viral density estimates is a highly efficient and well tolerated method of assessing SARS CoV-2 antiviral therapeutics in vivo.
Funding: 'Finding treatments for COVID-19: A phase 2 multi-centre adaptive platform trial to assess antiviral pharmacodynamics in early symptomatic COVID-19 (PLAT-COV)' is supported by the Wellcome Trust Grant ref: 223195/Z/21/Z through the COVID-19 Therapeutics Accelerator.
Clinical trial number: ClinicalTrials.gov (NCT05041907).
Data availability
All code and data are openly accessible via GitHub: https://github.com/jwatowatson/PLATCOV-IvermectinSequencing data have been deposited in GISAID.
-
PLATCOV Ivermectinhttps://github.com/jwatowatson/PLATCOV-Ivermectin.
Article and author information
Author details
William HK Schilling
Cintia Valeria Cruz
Janjira Thaipadungpanit
Mauro Martins Teixeira
Funding
Wellcome Trust (223195/Z/21/Z)
- Nicholas J White
Wellcome Trust (223195/Z/21/Z)
- William HK Schilling
Wellcome Trust (223195/Z/21/Z)
- William HK Schilling
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: The trial was approved by local and national research ethics boards in Thailand (Faculty of Tropical Medicine Ethics Committee, Mahidol University, FTMEC Ref: TMEC 21-058) and the Central Research Ethics Committee (CREC, Bangkok, Thailand, CREC Ref: CREC048/64BP-MED34) and by the Oxford University Tropical Research Ethics Committee (OxTREC, Oxford, UK, OxTREC Ref: 24-21). All patients provided fully informed written consent.
Copyright
© 2023, Schilling et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 6,384
- views
-
- 266
- downloads
-
- 14
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Citations by DOI
-
- 14
- citations for umbrella DOI https://doi.org/10.7554/eLife.83201
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Pharmacometrics of high dose ivermectin in early COVID-19: an open label, randomized, controlled adaptive platform trial (PLATCOV)
eLife 12:e83201.
https://doi.org/10.7554/eLife.83201
